Nail–Patella Syndrome: clinical and molecular data in 55 families raising the hypothesis of a genetic heterogeneity

Ghoumid, Jamal; Petit, Florence; Holder‐Espinasse, Muriel; Jourdain, Anne‐Sophie; Guerra, José; Dieux-Coëslier, Anne; Figeac, Martin; Porchet, Nicole; Manouvrier‐Hanu, Sylvie; Escande, Fabienne

doi:10.1038/ejhg.2015.77

Cited by 45 publications

(52 citation statements)

References 28 publications

(42 reference statements)

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“…For example, in typical phenotypes or easily recognizable syndromes (e.g., Nager Syndrome, EEC Syndrome, Tricho‐Rhino‐Phalangeal Syndrome, Robinow Syndrome, Nail‐Patella Syndrome, etc. ), the yield may raise up to 50% or even 100%, consistent with what is described in the literature for the targeted analysis of several conditions Nager syndrome (Bernier et al, ), Nail‐Patella syndrome (Ghoumid et al, ), SHFM (Sowińska‐Seidler, Socha, & Jamsheer, ), and EEC syndrome (Rinne, Hamel, Bokhoven, & Brunner, ). Careful clinical examination before and after molecular testing is crucial in some cases to assess the variant pathogenicity.…”

Section: Discussionsupporting

confidence: 83%

Multiplex targeted high‐throughput sequencing in a series of 352 patients with congenital limb malformations

et al. 2019

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Congenital limb malformations (CLM) comprise many conditions affecting limbs and more than 150 associated genes have been reported. Due to this large heterogeneity, a high proportion of patients remains without a molecular diagnosis. In the last two decades, advances in high throughput sequencing have allowed new methodological strategies in clinical practice. Herein, we report the screening of 52 genes/regulatory sequences by multiplex high‐throughput targeted sequencing, in a series of 352 patients affected with various CLM, over a 3‐year period of time. Patients underwent a clinical triage by expert geneticists in CLM. A definitive diagnosis was achieved in 35.2% of patients, the yield varying considerably, depending on the phenotype. We identified 112 single nucleotide variants and 26 copy‐number variations, of which 52 are novel pathogenic or likely pathogenic variants. In 6% of patients, variants of uncertain significance have been found in good candidate genes. We showed that multiplex targeted high‐throughput sequencing works as an efficient and cost‐effective tool in clinical practice for molecular diagnosis of congenital limb malformations. Careful clinical evaluation of patients may maximize the yield of CLM panel testing.

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Section: Discussionsupporting

confidence: 83%

Multiplex targeted high‐throughput sequencing in a series of 352 patients with congenital limb malformations

et al. 2019

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“…Autoregulation during development reinforces or stabilizes a transcriptional pattern of differentiation (Crews and Pearson, 2009). This could also be of clinical importance since a population of NPS patients with mutations linked to the LMX1B locus fail to demonstrate mutations in the LMX1B coding sequence (Ghoumid et al, 2016). The fact that NPS results from haploinsufficiency of LMX1B signifies that the functional level of LMX1B is crucial for normal development.…”

Section: Nail-patella Syndromementioning

confidence: 99%

Lmx1b-targeted cis-regulatory modules involved in limb dorsalization

et al. 2017

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Lmx1b is a homeodomain transcription factor responsible for limb dorsalization. Despite striking double-ventral (loss-of-function) and double-dorsal (gain-of-function) limb phenotypes, no direct gene targets in the limb have been confirmed. To determine direct targets, we performed a chromatin immunoprecipitation against Lmx1b in mouse limbs at embryonic day 12.5 followed by next-generation sequencing (ChIP-seq). Nearly 84% (=617) of the Lmx1b-bound genomic intervals (LBIs) identified overlap with chromatin regulatory marks indicative of potential -regulatory modules (PCRMs). In addition, 73 LBIs mapped to CRMs that are known to be active during limb development. We compared Lmx1b-bound PCRMs with genes regulated by Lmx1b and found 292 PCRMs within 1 Mb of 254 Lmx1b-regulated genes. Gene ontological analysis suggests that Lmx1b targets extracellular matrix production, bone/joint formation, axonal guidance, vascular development, cell proliferation and cell movement. We validated the functional activity of a PCRM associated with joint-related that provides a mechanism for Lmx1b-mediated joint modification and a PCRM associated with that suggests a role in autoregulation. This is the first report to describe genome-wide Lmx1b binding during limb development, directly linking Lmx1b to targets that accomplish limb dorsalization.

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“…It is characterized by dystrophic nails, hypoplastic or absent patellae, dysplasia of the iliac horn, and elbows. Almost all affected individuals (96% in one series) have nail dysplasia ; the dystrophy is usually more marked on the thumb and the degree of dystrophy usually diminishes towards the little finger. Koilonychias and longitudinal striations are the most common finding, followed by anonychia .…”

Section: Molecular Pathways In Nail Development and Homeostasismentioning

confidence: 99%

Genetics of syndromic and non‐syndromic hereditary nail disorders

et al. 2016

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The nail is a unique epithelial skin appendage made up of a fully keratinized nail plate. The nail can be affected in several systemic illnesses, dermatological diseases, and inherited nail disorders. Nail dystrophies can present as isolated disorders or as a part of syndromes. Substantial progress has been achieved in the management and diagnosis of nail diseases; however, not much is known about the underlying molecular controls of nail growth. The homeostasis and development of the nail appendage depend on the intricate interactions between the epidermis and underlying mesenchyme, and comprise different signaling pathways such as the WNT signaling pathway. Digit-tip regeneration in mice and humans has been a known fact for the past six decades; however, only recently the underlying biological mechanisms by which the nail organ achieves digit regeneration have been elucidated. Moreover, significant progress has been made in identifying nail stem cells and localizing stem cell niches in the nail unit. More fascinating, however, is the role they play in orchestrating the processes that lead to the regeneration of the digit. Further elucidating the role of nail stem cells and the signaling pathways driving epithelial-mesenchymal interactions in the nail unit might contribute to the development of novel therapeutic tools for amputees.

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Nail–Patella Syndrome: clinical and molecular data in 55 families raising the hypothesis of a genetic heterogeneity

Cited by 45 publications

References 28 publications

Multiplex targeted high‐throughput sequencing in a series of 352 patients with congenital limb malformations

Multiplex targeted high‐throughput sequencing in a series of 352 patients with congenital limb malformations

Lmx1b-targeted cis-regulatory modules involved in limb dorsalization

Genetics of syndromic and non‐syndromic hereditary nail disorders

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